Progesterone is a naturally occurring steroidal sex hormone also known as Pregn-4-ene-3,20-dione. Progesterone has been used to treat a variety of conditions, including hormonal deficiency of the corpus luteum. The present invention concerns a new dosage form of progesterone particularly suitable for the treatment of premenstrual syndrome.
A wide variety of pharmeceutical compositions containing progesterone and a carrier or vehicle for progesterone have been proposed. The following patents, for example, disclose a variety of compositions containing progesterone, progesterone derivatives or other steroids in a wide variety of carriers or vehicles: Himelick U.S. Pat. No. 2,557,052 issued June 12, 1951, Lee U.S. Pat. No. 2,675,342 issued Apr. 13, 1954, Masters U.S. Pat. No. 2,988,486 issued June 13, 1961, Lozinski U.S. Pat. No. 3,051,624 issued Aug. 28, 1962, Spero U.S. Pat. No. 3,230,142 issued Jan. 18, 1966, Ercoli U.S. Pat. No. 3,342,682 issued Sept. 19, 1967, Rudel U.S. Pat. No. 3,828,106 issued Aug. 6, 1974, van der Vies U.S. Pat. No. 4,083,973 issued Apr. 11, 1978, Herschler U.S. Pat. No. 4,177,267 issued Dec. 4, 1979, Hussain U.S. Pat. No. 4,383,993 issued May 17, 1983, Sherman U.S. Pat. No. 4,310,510 issued Jan. 12, 1982, Fried U.S. Pat. No. 3,288,679 issued Nov. 29, 1966, Siegrist U.S. Pat. No. 3,535,419 issued Oct. 20, 1970, Coulson U.S. Pat. No. 4,381,298 issued Apr. 26, 1983, Applezweig U.S. Pat. No. 3,409,721 issued Nov. 5, 1968, Pasquale U.S. Pat. No. 4,530,839 issued July 23, 1985, Pasquale U.S. Pat. No. 4,544,554 issued Oct. 1, 1985, Chatterton, Jr. U.S. Pat. No. 4,522,831 issued June 11, 1985 and Royer U.S. Pat. No. 4,349,530 issued Sept. 14, 1982. The following patents particularly concern compositions for administering progesterone orally: Meli U.S. Pat. No. 3,284,303 issued Nov. 8, 1966, Leeson U.S. Pat. No. 3,862,311 issued Jan. 21, 1975, Besins U.S. Pat. No. 4,196,188 issued Apr.1, 1980. The foregoing patent to Besins is particularly pertinent to the present invention insofar as it discloses a dosage form comprising capsules containing micronized progesterone in an oil vehicle.
It has long been recognized that oral administration of progesterone involves certain difficulties. For example, as described in the foregoing patents to Meli and Rudel, progesterone taken orally is absorbed in the small intestine but thereafter exhibits relatively progestational activity. Progesterone circulated through the liver is metabolized into other, inactive compounds. Progesterone is described as having a short "half-life" in the blood.
An essential problem in the treatment of premenstrual syndrome (PMS) is the administration of sufficient progesterone to increase the level in the blood to at least 10-12 nanograms per milliliter (ng/ml). A blood serum level in the range of 12 to 20 ng/ml is particularly desirable, since this is the normal level that occurs during the menstrual cycle.
In practice, it has proven very difficult to provide an oral formulation of progesterone which reaches and sustains a high blood serum progesterone level. The composition taught by the foregoing patent to Besins employs micronized particles of recrystallized progesterone. In the preferred embodiment of Besins, at least 80% of the particles preferably have a particle size in the range of from 5 to 15 microns. These particles are micronized in oil.
The present invention provides an orally administrable form of progesterone which, like the Besins composition, can be used to fill capsules, but is more easily prepared than the Besins composition. The pharmaceutical composition according to the present invention also exhibits a unusually high activity as reflected by both the peak level of progesterone blood serum concentration and the length of time a high blood serum concentration of progesterone is maintained after the composition is administered orally.